KCNE3 is a single transmembrane regulatory subunit that modulates voltage-gated potassium (Kv) channel function through direct association with pore-forming α subunits 1. Structurally, KCNE3 contains a transmembrane domain (residues 57-82) with an extracellular N-terminus and intracellular C-terminus 2. Its primary mechanism involves altering channel gating kinetics and enhancing complex stability; notably, KCNE3 suppresses KCNQ1 channel closure at negative membrane voltages by locking the voltage sensor in a depolarized conformation, while PIP2 signaling triggers pore dilation 3. KCNE3 associates with KCNQ1 to form constitutively active intestinal cAMP-stimulated potassium channels involved in chloride secretion 1, and with KCNC4 to establish resting membrane potential in skeletal muscle 1. Functionally, KCNE3 exhibits opposite regulatory effects compared to KCNE1 on KCNQ1 channels 1. Disease relevance includes Brugada syndrome 6 associated with KCNE3 mutations 1, though meta-analysis found no significant association between KCNE3 variants and Ménière's disease risk 4. KCNE3 is expressed in gastrointestinal tissues and embryonic capillary endothelium 5, with emerging evidence for cardiac effects through regulation of Kv4 channels 6.